The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Immunohematology and Blood Transfusion.
Aim and focus
The aim of the research program is to gain insight in the interaction between the immune system and tumors and to exploit this knowledge for the development of immune intervention strategies against cancer. A major focus of this work is the clinical application of concepts conceived through work in animal models: therapeutic anti-cancer modalities that make use of long synthetic peptides, Toll like receptor ligands, and immune modulatory therapeutics (e.g. antibodies like checkpoint blockers). Ongoing clinical studies with peptide-based vaccines target human papillomavirus (HPV) positive anogenital neoplasia and oropharyngeal cancers. Other tumor-specific target antigens are being evaluated for clinical application as well. These translational efforts are firmly based on preclinical research involving detailed analysis of the antigen-specific anti-cancer immune response in humans that provides crucial information concerning the immune stimulatory requirements of our clinical-grade vaccines. Fundamental research in mouse models aims to gain knowledge on the regulation of the anti-tumor immune response for further improvement of the efficacy of anti-cancer vaccines and interference with immune suppressive mechanisms in vivo.
Position in international context
The Tumor Immunology Group has a leading international position, in particular with respect to investigation of the interaction between tumors and the immune system in well-defined mouse tumor models, DC biology and antigen processing, the development of antigen-specific T cell responses, the design of well-defined synthetic vaccine modalities, the development and clinical application of peptide-based anti-cancer vaccines and the detailed analysis of human/mouse T-cell immunity against tumor antigens and the tumor micro-environment.
Content / highlights / achievements
- The demonstration that long peptide-based vaccines are superior in inducing therapeutic anti-tumor immunity in mice and of HPV-specific T-cell immunity in end-stage cervical cancer patients.
- The significant clinical benefit of patients with HPV-induced VIN lesions following therapeutic vaccination with synthetic long peptides harbouring HPV E6/E7 protein sequences.
- The sponsoring of further clinical research through foundation of the company ISA (Immune System Activation) in 2004, made possible by filing of patent applications describing the aforementioned concepts. Many of these patents have now been awarded.
- The synthetically defined and patented TLR2 ligand UPam, which improved potency of long peptide based vaccines by direct conjugation is in Phase I clinical trial in oropharyngeal cancer patients.
- The demonstration that local treatment of immune-modulatory antibodies in tumor-bearing mice are effective in with minimal side-effects.
- The demonstration that effective cancer immunity can be achieved by combination protocols of classical cancer treatment protocols like chemotherapy plus photodynamic-ablation therapies, and chemotherapy plus vaccination.
- The gain of knowledge on T cell fitness related to vaccines and immunotherapy; in particular the significance of autocrine IL-2 and costimulatory molecules (CD27, CD28, OX40, 4-1BB) and inhibitory molecules (CTLA-4, PD-1)
Future themesWithin the Tumor Immunology research cluster we will focus on combination cancer eradication protocols of immune therapy and classical ablation therapies or protocols to repolarize the suppressive environment of the tumor.
Our aims are to improve vaccinations strategies on the one hand and positively influence the tumor-milieu on the other.
Vaccination strategies will be improved by synthetic approaches to combine peptide vaccines with defined immune-stimulating molecules, DNA-based vaccines and formulations for in vivo delivery (collaboration the LIC and LACDR, UL). This will be further developed for GMP setting (KFT, LUMC). This will set the stage for not only long peptide based vaccines for defined tumor antigens but also for the recently explored neo-epitopes, which are mutated antigens occurring in many cancer patients exposed to external mutagenic pressure. By modern New Generation Exome Sequencing approaches these epitopes can be identified and are the perfect targets for personalized therapeutic vaccination strategies.
The suppressive tumor environment will be analysed in cellular and molecular detail. The different subsets of T cells, myeloid cell types and suppressive cytokines will be studied and approaches for combination therapies will be tested in our in vivo tumor models. Clinical success of blockade of co-inhibitory receptors PD-1 and CTLA-4 by specific antibodies as well as of agonistic antibodies targeting TNFR family members (e.g. CD27 and OX40) on tumor-specific T cells to reactivate anti-tumor immunity will be mechanistically and in-depth explored in our models to minimize unwanted side effects and optimize for therapy settings in combination with vaccination, chemotherapy, radio-ablation, adoptive T cell therapy (ACT) and surgery
Cohesion within LUMC
This research program is conducted in close collaboration with multiple groups within the LUMC, in particular with the Depts. of Medical Oncology, Gynecology, Pharmacy, Radiology and Pathology (HPV, cervical neoplasia, neo-epitopes), Surgery (colorectal cancer), and Human Genetics (genomics).